EP0291234A3 - Peptidic human leukocyte elastase (hle) inhibitors - Google Patents

Peptidic human leukocyte elastase (hle) inhibitors Download PDF

Info

Publication number
EP0291234A3
EP0291234A3 EP88304080A EP88304080A EP0291234A3 EP 0291234 A3 EP0291234 A3 EP 0291234A3 EP 88304080 A EP88304080 A EP 88304080A EP 88304080 A EP88304080 A EP 88304080A EP 0291234 A3 EP0291234 A3 EP 0291234A3
Authority
EP
European Patent Office
Prior art keywords
inhibitors
formula
hle
peptidic
human leukocyte
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP88304080A
Other versions
EP0291234B1 (en
EP0291234A2 (en
Inventor
Philip Duke Edwards
Joseph James Lewis
Charles William Perkins
Diane Amy Trainor
Richard Alan Wildonger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zeneca Inc
Original Assignee
ICI Americas Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB878711050A external-priority patent/GB8711050D0/en
Priority claimed from GB888803206A external-priority patent/GB8803206D0/en
Application filed by ICI Americas Inc filed Critical ICI Americas Inc
Priority to AT88304080T priority Critical patent/ATE103293T1/en
Publication of EP0291234A2 publication Critical patent/EP0291234A2/en
Publication of EP0291234A3 publication Critical patent/EP0291234A3/en
Application granted granted Critical
Publication of EP0291234B1 publication Critical patent/EP0291234B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a series of novel heterocyclic ketones of formula I <CHEM> and pharmaceutically acceptable base-addition salts thereof, in which the values of R<4>, L, A, X and Q have the meanings defined in the following specification. The compounds of formula I are inhibitors of human leukocytic elastase. The invention also provides pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable base-addition salt thereof, and processes and intermediates for the manufacture of compounds of formula I.
EP88304080A 1987-05-11 1988-05-05 Peptidic human leukocyte elastase (HLE) inhibitors Expired - Lifetime EP0291234B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88304080T ATE103293T1 (en) 1987-05-11 1988-05-05 HUMAN LEUKOCYTE ELASTASE (HLE) PEPTIDIC INHIBITORS.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB878711050A GB8711050D0 (en) 1987-05-11 1987-05-11 Selected heterocyclic ketones
GB8711050 1987-05-11
GB8803206 1988-02-11
GB888803206A GB8803206D0 (en) 1988-02-11 1988-02-11 Selected heterocyclic ketones

Publications (3)

Publication Number Publication Date
EP0291234A2 EP0291234A2 (en) 1988-11-17
EP0291234A3 true EP0291234A3 (en) 1990-08-22
EP0291234B1 EP0291234B1 (en) 1994-03-23

Family

ID=26292230

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88304080A Expired - Lifetime EP0291234B1 (en) 1987-05-11 1988-05-05 Peptidic human leukocyte elastase (HLE) inhibitors

Country Status (22)

Country Link
US (1) US5164371A (en)
EP (1) EP0291234B1 (en)
JP (1) JPS6445395A (en)
KR (1) KR880013926A (en)
CN (1) CN1037519A (en)
AT (1) ATE103293T1 (en)
AU (1) AU605284B2 (en)
CA (1) CA1326107C (en)
DE (1) DE3888568T2 (en)
DK (1) DK260588A (en)
ES (1) ES2063034T3 (en)
FI (1) FI91072C (en)
GB (1) GB8809316D0 (en)
HU (1) HU201963B (en)
IE (1) IE62524B1 (en)
IL (1) IL86236A (en)
NO (1) NO176519C (en)
NZ (1) NZ224452A (en)
PT (1) PT87454B (en)
SU (1) SU1678207A3 (en)
ZA (1) ZA883006B (en)
ZW (1) ZW4988A1 (en)

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8910547D0 (en) * 1989-05-08 1989-06-21 Ici America Inc Substituted ketones
GB8910550D0 (en) * 1989-05-08 1989-06-21 Ici America Inc Substituted amides
DE69129083T2 (en) * 1990-05-24 1998-07-09 Zeneca Ltd Therapeutic agent for the prevention and treatment of respiratory distress syndrome in adults
EP0458537B1 (en) * 1990-05-24 1999-03-31 Zeneca Limited Use of a therapeutic compound for the treatment of bronchitis
US5162348A (en) * 1990-05-24 1992-11-10 Imperial Chemical Industries Plc Treatment of cystic fibrosis
EP0475531B1 (en) * 1990-09-10 1995-01-18 Asahi Kasei Kogyo Kabushiki Kaisha Benzoic acid phenylester compounds and elastase inhibiting compositions containing the same
US6100238A (en) * 1994-11-21 2000-08-08 Cortech Inc. Indole and tetrahydroisoquinoline containing Alpha-keto oxadiazoles as serine protease inhibitors
US5618792A (en) * 1994-11-21 1997-04-08 Cortech, Inc. Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase
US6001813A (en) * 1994-11-21 1999-12-14 Cortech Inc. Val-pro containing α-keto oxadiazoles as serine protease inhibitors
US6001811A (en) * 1994-11-21 1999-12-14 Cortech Inc. Serine protease inhibitors--N-substituted derivatives
US5998379A (en) * 1994-11-21 1999-12-07 Cortech Inc. Serine protease inhibitors-proline analogs
US6150334A (en) * 1994-11-21 2000-11-21 Cortech, Inc. Serine protease inhibitors-tripeptoid analogs
US6001814A (en) * 1994-11-21 1999-12-14 Cortech Inc. Serine protease inhibitors
US6015791A (en) * 1994-11-21 2000-01-18 Cortech Inc. Serine protease inhibitors-cycloheptane derivatives
US20020119985A1 (en) 1994-11-21 2002-08-29 Albert Gyorkos Serine protease inhibitors
US6159938A (en) * 1994-11-21 2000-12-12 Cortech, Inc. Serine protease inhibitors comprising α-keto heterocycles
US5556990A (en) * 1994-12-16 1996-09-17 Rhone-Poulenc Rorer Pharmaceuticals Inc. Polyarylcarbamoylaza- and -carbamoylalkanedioic acids
US6017887A (en) * 1995-01-06 2000-01-25 Sibia Neurosciences, Inc. Peptide, peptide analog and amino acid analog protease inhibitors
US5804560A (en) * 1995-01-06 1998-09-08 Sibia Neurosciences, Inc. Peptide and peptide analog protease inhibitors
US6063794A (en) 1996-10-11 2000-05-16 Cor Therapeutics Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
AU741099B2 (en) * 1997-04-14 2001-11-22 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
NZ500353A (en) 1997-04-14 2002-02-01 Cor Therapeutics Inc Cyclic diaza compounds that are selective inhibitors of factor Xa
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6274602B1 (en) * 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6177572B1 (en) 1997-08-20 2001-01-23 Sepracor, Inc. Solid and liquid-phase synthesis of benzoxazoles and benzothiazoles and their use
US6656910B2 (en) 1997-12-04 2003-12-02 Cortech, Inc. Serine protease inhibitors
US6184377B1 (en) 1997-12-15 2001-02-06 Sepracor Inc. Compositions containing N-amino- and N-hydroxy-quinazolinones and methods for preparing libraries thereof
JP2003520185A (en) * 1998-06-03 2003-07-02 コーテック インコーポレーテッド Α-Ketooxadiazoles as serine protease inhibitors
JP2000256396A (en) 1999-03-03 2000-09-19 Dainippon Pharmaceut Co Ltd Heterocyclic compound, its intermediate and elastase inhibitor
TW200404789A (en) 1999-03-15 2004-04-01 Axys Pharm Inc Novel compounds and compositions as protease inhibitors
WO2000056724A1 (en) * 1999-03-22 2000-09-28 The Board Of Governors For Higher Education, State Of Rhode Island And Providence Plantations Oxazole and thiazole combinatorial libraries
AU5625900A (en) * 1999-06-17 2001-01-09 Cortech, Inc. Method and compounds for inhibiting activity of serine elastases
MXPA03005601A (en) 2000-12-22 2004-12-02 Axys Pharm Inc Novel compounds and compositions as cathepsin inhibitors.
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
CN1324008C (en) 2001-09-14 2007-07-04 安万特药物公司 Novel compounds and compositions as cathepsin inhibitors
WO2003042197A1 (en) 2001-11-14 2003-05-22 Aventis Pharmaceuticals Inc. Oligopeptides and compositions containing them as cathepsin s inhibitors
US7091360B2 (en) * 2002-04-16 2006-08-15 Aventis Pharma S.A. Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof
JP3744890B2 (en) 2002-11-01 2006-02-15 ハッピー工業株式会社 sewing machine
DE102004045648A1 (en) * 2004-09-21 2006-03-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg New betamimetics for the treatment of respiratory diseases
KR101069051B1 (en) 2006-05-23 2011-09-29 아이알엠 엘엘씨 Compounds and compositions as channel activating protease inhibitors
WO2008060621A2 (en) * 2006-11-17 2008-05-22 Abbott Laboratories Aminopyrrolidines as chemokine receptor antagonists
BRPI0807483A2 (en) 2007-02-09 2014-05-13 Irm Llc COMPOUNDS AND COMPOSITIONS AS CHANNEL ACTIVATE PROTEASE INHIBITORS
FR2914920B1 (en) 2007-04-11 2011-09-09 Clariant Specialty Fine Chem F PROCESS FOR DEACETALIZING ALPHA-AMINOACETALS
FR2916441B1 (en) 2007-05-22 2009-08-28 Clariant Specialty Fine Chem PROCESS FOR RACEMIZING OPTICALLY ACTIVE ALPHA-AMINOACETALS
JP2010533144A (en) * 2007-07-10 2010-10-21 プロビオドルグ エージー New compounds
US20090156509A1 (en) * 2007-12-12 2009-06-18 Accuthera, Inc. Tri-peptide Inhibitors of Serine Elastases
FR2927900B1 (en) 2008-02-27 2010-09-17 Clariant Specialty Fine Chem PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE ALPHA-AMINOACETALS

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0124317A2 (en) * 1983-04-27 1984-11-07 Ici Americas Inc. Proline derivatives
EP0189305A2 (en) * 1985-01-22 1986-07-30 Ici Americas Inc. Peptide derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4643991A (en) * 1984-12-18 1987-02-17 The University Of Kentucky Research Foundation Peptide elastase inhibitors and methods
DE3683541D1 (en) * 1985-06-07 1992-03-05 Ici America Inc SELECTED DIFLUOR COMPOUNDS.
AU625292B2 (en) * 1988-09-09 1992-07-09 Czechoslovak Academy Of Sciences Elastase inhibiting polymers and methods
GB8910547D0 (en) * 1989-05-08 1989-06-21 Ici America Inc Substituted ketones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0124317A2 (en) * 1983-04-27 1984-11-07 Ici Americas Inc. Proline derivatives
EP0189305A2 (en) * 1985-01-22 1986-07-30 Ici Americas Inc. Peptide derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 95, no. 25, 21st December 1981, page 223, abstract no. 216963a, Columbus, Ohio, US; B.M. ASHE et al.: "Selective inhibition of human leukocyte elastase and bovine alpha-chymotrypsin by novel heterocycles", & J. BIOL. CHEM. 1981, 256(22), 11603-6 *
CHEMICAL ABSTRACTS, vol. 97, no. 7, 16th August 1982, page 268, abstract no. 51652z, Columbus, Ohio, US; T. TESHIMA et al.: "A new class of heterocyclic serine protease inhibitors. Inhibition of human leukocyte elastase, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin A, with substituted benzoxazinones, quinazolines, and anthranilates", & J. BIOL. CHEM. 1982, 257(9), 5085-91 *

Also Published As

Publication number Publication date
PT87454B (en) 1992-08-31
DK260588D0 (en) 1988-05-11
FI882176A0 (en) 1988-05-10
EP0291234B1 (en) 1994-03-23
ZA883006B (en) 1988-11-11
JPS6445395A (en) 1989-02-17
FI91072C (en) 1994-05-10
SU1678207A3 (en) 1991-09-15
DK260588A (en) 1988-11-12
DE3888568D1 (en) 1994-04-28
PT87454A (en) 1989-05-31
EP0291234A2 (en) 1988-11-17
KR880013926A (en) 1988-12-22
CA1326107C (en) 1994-01-11
ATE103293T1 (en) 1994-04-15
CN1037519A (en) 1989-11-29
IL86236A (en) 1994-12-29
HUT46708A (en) 1988-11-28
ZW4988A1 (en) 1989-12-06
NO176519B (en) 1995-01-09
NO176519C (en) 1995-04-19
GB8809316D0 (en) 1988-05-25
HU201963B (en) 1991-01-28
NZ224452A (en) 1991-06-25
NO882036D0 (en) 1988-05-10
IL86236A0 (en) 1988-11-15
IE62524B1 (en) 1995-02-08
US5164371A (en) 1992-11-17
IE881416L (en) 1988-11-11
ES2063034T3 (en) 1995-01-01
AU1539088A (en) 1988-11-17
AU605284B2 (en) 1991-01-10
FI882176A (en) 1988-11-12
NO882036L (en) 1988-11-14
DE3888568T2 (en) 1994-07-21
FI91072B (en) 1994-01-31

Similar Documents

Publication Publication Date Title
EP0291234A3 (en) Peptidic human leukocyte elastase (hle) inhibitors
DE69232022D1 (en) Naphthyridine derivatives as angiotensin II antagonist inhibitors
EP0976748A4 (en) Pyrrolidine derivatives having phospholipase a2 inhibitory activity
TW280813B (en)
EP0276101A3 (en) Substituted peptide derivatives
TW221429B (en)
NZ227682A (en) Thioformamide derivatives, preparation thereof and pharmaceutical compositions
EP0489925A4 (en) Pyrimidine compound and pharmaceutically acceptable salt thereof
GR3019145T3 (en) Fungicidal furanone derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

RHK1 Main classification (correction)

Ipc: C07K 5/06

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

17P Request for examination filed

Effective date: 19900903

17Q First examination report despatched

Effective date: 19921211

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ZENECA INC.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE ES FR GB GR IT LI LU NL SE

REF Corresponds to:

Ref document number: 103293

Country of ref document: AT

Date of ref document: 19940415

Kind code of ref document: T

ITF It: translation for a ep patent filed
REF Corresponds to:

Ref document number: 3888568

Country of ref document: DE

Date of ref document: 19940428

REG Reference to a national code

Ref country code: GR

Ref legal event code: FG4A

Free format text: 3011216

ET Fr: translation filed
EPTA Lu: last paid annual fee
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2063034

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

EAL Se: european patent in force in sweden

Ref document number: 88304080.0

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19950512

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 19950530

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19950531

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19950601

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19950613

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19960505

Ref country code: AT

Effective date: 19960505

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19960517

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19960531

BERE Be: lapsed

Owner name: ZENECA INC.

Effective date: 19960531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 19961130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19961201

REG Reference to a national code

Ref country code: GR

Ref legal event code: MM2A

Free format text: 3011216

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 19961201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19970506

EUG Se: european patent has lapsed

Ref document number: 88304080.0

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20050406

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20050517

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20050518

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20050531

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20050613

Year of fee payment: 18

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060505

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060506

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060531

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060531

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20060531

Year of fee payment: 19

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061201

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20060505

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20070131

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20060506

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20070505